Structure-activity relationships in a series of dihydrobenzofuran derivatives related structurally to the 5-HT 3 antagonist and 5-HT 4 agonist ADR 932 (1) were investigated. Members of this series, such as (18) and (23), were found to be 5-HT 4 agonists or partial agonists endowed with remarkably high affinity and selectivity.Serotonin (5-HT) is a neurotransmitter involved in a wide range of pharmacological effects. Four broad classes of 5-HT receptors are currently recognised (5-HT l, 5-HT 2, 5-HT 3 and 5-HT4), and several new receptor clones, termed 5-HT 5, 5-HT 6 and 5-HT 7, have been identified. Antagonists of the 5-HT 3 receptor subtype are used clinically for the treatment of chemotherapy or radiotherapy-induced nausea and vomiting. Further therapeutic indications such as control of pain, anxiety and depression, memory impairment and drug withdrawal are being currently investigated. Pharmacological responses mediated by the 5-HT 4 receptor subtype have been identified in the CNS, the gastrointestinal tract, and the heart. In addition to the gastric prokinetic activity of the benzamide derivatives such as cisapride, renzapride and zacopride, which has been related to the activation of the 5-HT 4 receptor, a wide range of other therapeutic targets for modulators of this receptor can be envisaged, including migraine, IBS (irritable bowel syndrome), arrhythmias, anxiety, and memory and/or learning dysfunctions. In the course of our work on the synthesis and evaluation of novel serotonergic agents, ADR-932 (1) was identified as a potent, long-lasting and orally active 5-HT 3 antagonist.Similarly to other 5-HT 3 antagonists of its generation, ADR-932 also shows relatively potent agonist activity at the 5-HT 4 receptor (Table 1). ADR-932 significantly increases gastric emptying when orally or intravenously administered to dogs. This paper describes the discovery of a novel series of 5-HT 4 agonists endowed with very high affinity and selectivity following a systematic manipulation of the structure starting from the dual activity of 1. Structure-activity relationships were explored by variation of the substituents at positions 4, 5 and 7 of the dihydrobenzofuran ring and some requirements for the activities became apparent.